The novel biguanide derivative 4C synergizes with talazoparib by inducing ferroptosis via the SREBP1/FASN/ SLC7A11/GPX4 axis in bladder cancer.

Bladder cancer (BC) remains a clinically challenging urothelial malignancy, largely because a substantial proportion of patients have no effective treatment options. Epidemiological studies have shown that metformin can improve the survival rate of cancer patients. However, its clinical application is limited by the requirement of high concentrations to exert antitumor effects. To overcome this limitation, we modified and optimized the biguanide structure using the intermediate derivatization methods and obtained a novel biguanide derivative 4C. Our study revealed that 4C suppressed the expression of sterol regulatory element-binding protein 1 (SREBP1), thereby inhibiting the transcription of fatty acid synthase (FASN) and downregulating its protein expression. Concurrently, 4C inhibited the expression of ferroptosis-related regulatory proteins NRF2, SLC7A11, and GPX4, induced ferroptosis and effectively suppressed the proliferation and migration of BC cells. Notably, this inhibitory effect was markedly attenuated by the ferroptosis-specific inhibitor ferrostatin-1. Furthermore, we found that inducing ferroptosis was an effective approach to sensitize BRCA1/2 wild-type BC cells to poly (ADP-ribose) polymerase (PARP) inhibitors. Accordingly, 4C enhanced the sensitivity of BC cells to the PARP inhibitor talazoparib by reducing glutathione (GSH) levels, promoting reactive oxygen species (ROS) accumulation, and increasing malondialdehyde (MDA) levels. However, in the presence of ferrostatin-1, the sensitizing effect of 4C on talazoparib was reversed. In conclusion, this study demonstrated that the combination of 4C and talazoparib induces ferroptosis via the SREBP1/FASN axis, providing a promising novel combination therapeutic strategy for the treatment of BC.